JP2015057422A - Tablet containing irbesartan - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet that contains irbesartan, and has quick tablet disintegration properties.SOLUTION: A tablet density is adjusted to improve tablet disintegration properties. Particularly, a tablet density is set to 1.12-1.23 mg/mmto obtain quick disintegration properties.

Description

  The present invention relates to tablets containing irbesartan, in particular tablets having good disintegration by controlling the density of the tablets.

  Hypertension treatment is mainly pharmacological treatment. In Japan, renin angiotensin (RA) such as diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (hereinafter also referred to as ARBs). ) Various antihypertensive drugs such as system inhibitors and beta blockers are used.

  Among these, angiotensin II receptor antagonists are useful, among them irbesartan, ie 2-n-butyl-4-spirocyclopentane-1-[(2 ′-(tetrazol-5-yl) biphenyl-4- Yl) methyl] -2-imidazolin-5-one is an effective long-acting angiotensin II receptor antagonist and is particularly useful in the treatment of cardiovascular diseases such as hypertension and heart failure.

  As a preparation of irbesartan, a tablet is known (Patent Document 1). However, if the solubility of irbesartan in water is low and the content of irbesartan in the preparation increases, the tablet size increases and the disintegration time of the tablet may be prolonged. When the disintegration time of the tablet is prolonged, the absorbability of irbesartan may be lowered, and the absorption may vary. Patent Document 1 does not describe a preparation with improved disintegration.

  As means for improving the disintegration time of the tablet, there are cases where the type and amount of additives in the tablet are changed (Patent Documents 2 and 3). However, depending on the additive used, the drug may decompose or conversely the disintegration time may be extended.

JP-A-8-333253 Special table 2003-176242 Special table 2005-533045

  Accordingly, there has been a demand for the development of a tablet capable of increasing the content of irbesartan, increasing the tablet size, and preventing the delay of disintegration time regardless of the type and amount of the tablet additive.

As a result of intensive studies to prevent a delay in disintegration time of tablets containing irbesartan, the present inventors have made the effect remarkable by setting the tablet density to 1.12 to 1.23 mg / mm ^3. It is.

That is, the present invention
(1) Contains irbesartan and croscarmellose sodium as a disintegrant, has a tablet density of 1.12 to 1.23 mg / mm ³ , an irbesartan content of 180 to 220 mg, and a total tablet weight of 380 to 430 mg tablet,
(2) The tablet according to (1) above, wherein the tablet volume is 320 to 360 mm ³ ;
(3) The tablet according to (1) above, wherein the tablet has a band thickness of 2.5 to 2.9 mm,
(4) The tablet according to (1) above, wherein the tablet has a thickness of 4.7 to 5.1 mm.
(5) The tablet according to (1) above, wherein the tablet volume is 320 to 360 mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness is 4.7 to 5.1 mm,
(6) The tablet according to any one of (1) to (5), further comprising lactose, crystalline cellulose, hypromellose, light anhydrous silicic acid, and magnesium stearate,
(7) Further, containing lactose, crystalline cellulose, hypromellose, light anhydrous silicic acid and magnesium stearate, the tablet volume is 320 to 360 mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness is The tablet according to any one of (1) to (5), which is 4.7 to 5.1 mm;
(8) The tablet according to any one of (1) to (7), wherein the disintegration time of the tablet is within 7 minutes,
(9) In the first solution of the Japanese Pharmacopoeia dissolution test, the tablet according to any one of (1) to (8) above, wherein the dissolution rate of irbesartan after 30 minutes from the start of the dissolution test is 85% or more,
(10) In the second solution of the Japanese Pharmacopoeia dissolution test, the tablet according to any one of (1) to (8) above, wherein the dissolution rate of irbesartan after 30 minutes from the start of the dissolution test is 70% or more,
(11) In the Japanese Pharmacopoeia dissolution test 1st liquid, the dissolution rate of irbesartan 30 minutes after the start of dissolution test is 85% or more, and in the Japanese Pharmacopoeia dissolution test 2nd liquid, irbesartan 30 minutes after the start of dissolution test The tablet according to any one of (1) to (8), wherein the dissolution rate of
(12) A film-coated tablet obtained by coating the tablet according to any one of (1) to (11) with hypromellose,
About.

  The disintegration time of the irbesartan-containing preparation of the present invention (hereinafter referred to as “present preparation”) is fast. In addition, the tablet has excellent hardness that can withstand practicality.

The figure which looked at the tablet used in the example from the side Disintegration time of tablets containing irbesartan when changing the density of tablets

In this specification, irbesartan means irbesartan, a pharmaceutically acceptable salt thereof, or a solvate thereof. The preparation of irbesartan is described in US Pat. No. 5,270,317 to Baunhart et al.
The chemical structural formula of irbesartan is shown below.

  The content of irbesartan in this preparation may be an amount that produces a medicinal effect. Specifically, it is 30 to 70% by weight, preferably 40 to 60% by weight, more preferably 45 to 55% by weight, based on the total amount of the preparation. Moreover, as a weight of the irbesartan in a formulation, it is 180-220 mg, Preferably, it is 185-215 mg, More preferably, it is 190-210 mg. If the weight of these preparations is larger, the tablet ingestion itself becomes difficult, and if it is less, it may be difficult to design the preparation by blending the active ingredient in one tablet.

As a drug of this preparation, a diuretic can be used in combination with irbesartan. As diuretics, trichloromethiazide, hydrochlorothiazide, chlorothiazide, hydroflumethiazide, bendroflumethiazide, methiclotiazide, polythiazide, xipamide, cyclopenthiazide, cyclothiazide and the like are known. Among these, trichlormethiazide is a typical thiazide antihypertensive diuretic and is marketed as fluuitran ^(R) .

  As a drug of this preparation, a calcium antagonist can be used in combination with irbesartan. Amlodipine, nifedipine, nicardipine and the like are known as calcium antagonists. Among them, amlodipine is a typical calcium antagonist.

  The form of the drug combination includes any form when the diuretic or calcium antagonist is used together, when used as a kit, or when contained as a combination drug. From the viewpoint of improving compliance through simplification of medication, a pharmaceutical formulated as a combination drug is preferable.

  It is desirable to set the dose of the medicament of the present invention in consideration of the patient's age, weight, disease type and degree, administration route, and the like. The dose of this preparation is usually about 50 to 200 mg as irbesartan per day per adult, although it depends on the severity and age of the patient.

The formulation can be defined by the density of the tablet. The tablet density can be calculated by dividing the tablet mass by the tablet volume, and can be measured by tablet volume / surface area simulation software (Tablet CAD). The density of the tablet in this preparation is 1.12 to 1.23 mg / mm ³ , preferably 1.13 to 1.23 mg / mm ³ , more preferably 1.15 to 1.23 mg / mm ³ . If it is different from the density range of the tablet, the disintegration time of the tablet may be prolonged.

  The formulation can be defined by the band thickness of the tablet. “Band thickness” refers to the height of the flat part on the side of the tablet and can be measured with calipers. The band thickness of the tablet in this preparation is 2.5 to 2.9 mm, preferably 2.5 to 2.85 mm, more preferably 2.5 to 2.8 mm. If it is different from the tablet thickness range, the tablet disintegration time may be extended.

  The formulation can be defined by the thickness of the tablet. The tablet thickness represents the length from the uppermost part of the round part of the tablet (cup depth) to the lowest part of the rounded part on the opposite side, and can be measured by a thickness gauge. The tablet thickness in this preparation is 4.7 to 5.1 mm, preferably 4.7 to 5.05 mm, and more preferably 4.7 to 5.0 mm. If it is different from the tablet thickness range, the tablet disintegration time may be extended.

The formulation can be defined by the tablet volume. The tablet volume can be measured by tablet volume / surface area simulation software (Tablet CAD). The volume of the tablet in this preparation is 325-360 mm < ³ >, Preferably it is 325-350 mm < ³ >, More preferably, it is 325-345 mm < ³ >. If it is different from the tablet volume range, the disintegration time of the tablet may be prolonged.

The formulation can be defined by the surface area of the tablet. The tablet surface area can be measured by tablet volume / surface area simulation software (Tablet CAD). The surface area of the tablet in the present preparation is 275 to 290 mm ² , preferably 275 to 287 mm ² , more preferably 275 to 285 mm ² . If the surface area of the tablet is different, the disintegration time of the tablet may be delayed.

  The formulation contains a disintegrant. As the disintegrating agent, those listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Pharmaceutical Standards, the Pharmaceutical Additives Standard, etc. can be used. Specifically, croscarmellose sodium (FMC-Asahi Kasei), crospovidone, carmellose calcium (Gotoku Pharmaceutical), sodium carboxymethyl starch (Matsutani Chemical Co., Ltd., Kimura Sangyo Co., Ltd.), low-substituted hydroxypropylcellulose Croscarmellose sodium is preferable.

  The content of the disintegrant in this preparation is 0.5 to 10% by weight, preferably 0.75 to 9% by weight, more preferably 1 to 8% by weight, based on the total amount of the preparation. If the content is higher than these, the tablet hardness may be lowered or the tablet size may be increased, which may cause problems in taking the medicine. If the content is lower, the disintegration time of the tablet may be prolonged.

  The preparation may contain an excipient, and an agent listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals or the Standards for Pharmaceutical Additives, etc. can be used. Specific excipients include lactose, crystalline cellulose, fructose, purified sucrose, sucrose, purified sucrose spherical granules, anhydrous lactose, sucrose / starch spherical granules, semi-digested starch, glucose, glucose hydrate, powdered sugar , Pullulan, β-cyclodextrin, aminoethylsulfonic acid, candy powder, sodium chloride, citric acid, sodium citrate, glycine, calcium gluconate, L-glutamine, tartaric acid, potassium hydrogen tartrate, ammonium carbonate, dextran 40, dextrin, Calcium lactate, povidone, macrogol (polyethylene glycol) 1500, macrogol 1540, macrogol 4000, macrogol 6000, anhydrous citric acid, DL-malic acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate L-aspartic acid Alginate, carmellose sodium, hydrous silicon dioxide, crospovidone, calcium glycerophosphate, magnesium silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, wheat flour, wheat starch, wheat germ powder, wheat Germ oil, rice flour, rice starch, cellulose acetate phthalate, titanium oxide, magnesium oxide, dihydroxyaluminum aminoacetate, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, natural aluminum silicate, corn starch, corn starch Granulated product, potato starch, hydroxypropyl cellulose, hydroxypropyl starch, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulated product, Examples thereof include calcium dihydrogenate, and lactose and crystalline cellulose are preferable.

  The content of the excipient in this preparation is 20 to 70% by weight, preferably 25 to 60% by weight, more preferably 30 to 50% by weight, based on the total amount of the preparation.

  This preparation may contain a binder, and a binder listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals or the Standards for Pharmaceutical Additives, etc. can be used. Specifically, hypromellose, corn starch, pregelatinized starch, partially pregelatinized starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose, carboxymethylethylcellulose, carmellose, Carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and the like can be mentioned, and hypromellose is preferable.

  The content of the binder in this preparation is 0.5 to 10% by weight, preferably 0.75 to 5% by weight, more preferably 1 to 4% by weight, based on the total amount of the preparation.

  This preparation may contain a fluidizing agent, and binders listed in Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards for Pharmaceuticals or Pharmaceutical Additives Standard, etc. can be used. Specific examples include light anhydrous silicic acid, hydrous silicon dioxide, talc and the like, and light anhydrous silicic acid is preferred.

  The content of the fluidizing agent in this preparation is 0.2 to 5% by weight, preferably 0.3 to 4.5% by weight, more preferably 0.5 to 4% by weight, based on the total amount of the preparation.

  This preparation may contain a lubricant, and a lubricant listed in Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards for Pharmaceuticals or Standards for Pharmaceutical Additives, etc. can be used. Specific examples include metal stearates, sucrose fatty acid esters, talc, hydrous silicon dioxide, and the like, with metal stearates being preferred. Examples of the metal stearate include magnesium stearate (Taipei Chemical Industry, Nippon Oil & Fats, Sakai Chemical Industry), calcium stearate (Kanto Chemical, Nippon Oil & Fats, Sakai Chemical Industry), etc., preferably magnesium stearate. .

  The content of the lubricant in the preparation is 0.2 to 5% by weight, preferably 0.3 to 4.5% by weight, more preferably 0.5 to 4% by weight, based on the total amount of the preparation.

  In this preparation, the total weight per tablet is 350 to 450 mg, preferably 380 to 430 mg, more preferably 390 to 420 mg. Above these weights, the tablets can be large and difficult to take.

As one form of this preparation, it contains irbesartan and a disintegrant, the tablet density is 1.12 to 1.23 mg / mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness is 4 0.7 to 5.1 mm, tablet volume of 325 to 360 mm ³ , preferably containing irbesartan and disintegrant, tablet density 1.13 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.85 mm, tablet thickness 4.7 to 5.05 mm, tablet volume 325 to 350 mm ³ , more preferably irbesartan and disintegrant, tablet density 1.15 to 1.23 mg / mm ³ The band thickness of the tablet is 2.5 to 2.8 mm, the tablet thickness is 4.7 to 5.0 mm, and the tablet volume is 325 to 345 mm ³ .

One of the forms of this preparation contains irbesartan, as disintegrant, one or more selected from croscarmellose sodium, crospovidone, carmellose calcium, sodium carboxymethyl starch and low-substituted hydroxypropylcellulose, and the density of the tablet 1.12 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.9 mm, tablet thickness 4.7 to 5.1 mm, tablet volume 325 to 360 mm ³ , preferably irbesartan, As a disintegrant, it contains one or more selected from croscarmellose sodium, crospovidone, carmellose calcium, sodium carboxymethyl starch and low-substituted hydroxypropylcellulose, and the density of the tablet is 1.13 to 1.23 mg / mm ³ The band thickness of the tablet is 2.5 ~ .85Mm, the thickness of the tablet 4.7~5.05mm, 325~350mm the volume of the tablet ^3, and more preferably irbesartan, as disintegrants include croscarmellose sodium, crospovidone, carmellose calcium, sodium carboxymethyl starch and It contains one or more selected from low-substituted hydroxypropylcellulose, the tablet density is 1.15 to 1.23 mg / mm ³ , the tablet band thickness is 2.5 to 2.8 mm, and the tablet thickness is 4.7. ˜5.0 mm, the tablet volume is 325 to 345 mm ³ .

As one form of this preparation, it contains irbesartan and croscarmellose sodium, the tablet density is 1.12 to 1.23 mg / mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness 4.7 to 5.1 mm, the tablet volume is 325 to 360 mm ³ , preferably irbesartan and croscarmellose sodium, the tablet density is 1.13 to 1.23 mg / mm ³ , and the tablet band thickness is 2.5 to 2.85 mm, tablet thickness 4.7 to 5.05 mm, tablet volume 325 to 350 mm ³ , more preferably irbesartan and croscarmellose sodium, tablet density 1.15 1.23 mg / mm ^3, the band thickness of the tablet 2.5～2.8Mm, the thickness of the tablet 4.7～5.0Mm, the volume of the tablet 325～345Mm ³ A.

As one of the forms of this preparation, it contains 30 to 70% by weight of irbesartan and 0.5 to 10% by weight of croscarmellose sodium with respect to the total amount of the preparation, and the tablet density is 1.12 to 1.23 mg / mm ³ , tablet band thickness 2.5-2.9 mm, tablet thickness 4.7-5.1 mm, tablet volume 325-360 mm ³ , preferably 40-60 wt% irbesartan, 0.75 Containing -9% by weight croscarmellose sodium, tablet density 1.13 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.85 mm, tablet thickness 4.7 to 5 .05mm, 325~350mm the volume of the tablet ^3, and more preferably 45 to 55 wt% of irbesartan, contain croscarmellose sodium 1-8 wt%, the density of the tablet is from 1.15 to 1 23 mg / mm ^3, the band thickness of the tablet 2.5～2.8Mm, is the thickness of the tablet 4.7～5.0Mm, the volume of the tablet is 325~345mm ^3.

As one form of this preparation, 180 to 220 mg of irbesartan and 0.5 to 10% by weight of croscarmellose sodium are contained in a tablet having a total weight per tablet of 380 to 430 mg, and the density of the tablet is 1.12 to 1.23 mg / mm ³ , tablet band thickness of 2.5 to 2.9 mm, tablet thickness of 4.7 to 5.1 mm, tablet volume of 325 to 360 mm ³ , preferably per tablet Containing 185 to 215 mg of irbesartan and 0.75 to 9% by weight of croscarmellose sodium, and the tablet density is 1.13 to 1.23 mg / mm ³ , and the tablet has a total weight of 385 to 425 mg band thickness 2.5～2.85Mm, the thickness of the tablet 4.7～5.05Mm, the volume of the tablet 325~350mm ^3, more preferably per tablet Weight relative to tablets 390～420Mg, irbesartan 190～210Mg, contain croscarmellose sodium 1-8 wt%, the density of the tablet is 1.15~1.23mg / mm ^3, the band thickness of the tablet 2.5 to 2.8 mm, the tablet thickness is 4.7 to 5.0 mm, and the tablet volume is 325 to 345 mm ³ .

One of the forms of this preparation contains irbesartan, croscarmellose sodium, lactose, crystalline cellulose, hypromellose, light anhydrous silicic acid and magnesium stearate, and the tablet density is 1.12 to 1.23 mg / mm ³ , The tablet band thickness is 2.5 to 2.9 mm, the tablet thickness is 4.7 to 5.1 mm, and the tablet volume is 325 to 360 mm ³ , preferably irbesartan, croscarmellose sodium, lactose, crystalline cellulose, hypromellose, Contains light anhydrous silicic acid and magnesium stearate, tablet density 1.13 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.85 mm, tablet thickness 4.7 to 5. 05Mm, the volume of the tablet 325～350Mm ^3, more preferably irbesartan, croscarmellose Thorium, lactose, crystalline cellulose, hypromellose, containing light anhydrous silicic acid and magnesium stearate, the density of the tablet 1.15~1.23mg / mm ^3, the band thickness of the tablet 2.5～2.8Mm, tablets The thickness is 4.7 to 5.0 mm, and the volume of the tablet is 325 to 345 mm ³ .

As one form of the preparation, 30 to 70% by weight of irbesartan, 0.5 to 10% by weight of croscarmellose sodium, 20 to 70% by weight of lactose and crystalline cellulose, 0.5 to Containing 10% by weight hypromellose, 0.2-5% by weight light silicic anhydride and 0.2-5% by weight magnesium stearate, tablet density 1.12-1.23 mg / mm ³ Band thickness of 2.5-2.9 mm, tablet thickness of 4.7-5.1 mm, tablet volume of 325-360 mm ³ , preferably 40-60 wt% irbesartan, 0.75-9 wt% Croscarmellose sodium, 25-60 wt% lactose and crystalline cellulose, 0.75-5 wt% hypromellose, 0.3-4.5 wt% light anhydrous silicic acid and 3 to 4.5 wt% magnesium stearate, tablet density 1.13 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.85 mm, tablet thickness 4.7 ˜5.05 mm, tablet volume 325-350 mm ³ , more preferably 45-55 wt% irbesartan, 1-8 wt% croscarmellose sodium, 30-50 wt% lactose and crystalline cellulose, 1-4 Containing 5% by weight of hypromellose, 0.5-4% by weight of light anhydrous silicic acid and 0.5-4% by weight of magnesium stearate, the density of the tablets being 1.15-1.23 mg / mm ³ , The band thickness is 2.5 to 2.8 mm, the tablet thickness is 4.7 to 5.0 mm, and the tablet volume is 325 to 345 mm ³ .

As one form of this preparation, 180 to 220 mg of irbesartan, 0.5 to 10% by weight of croscarmellose sodium, and 20 to 70% by weight of lactose per tablet having a total weight per tablet of 380 to 430 mg And crystalline cellulose, 0.5 to 10% by weight hypromellose, 0.2 to 5% by weight light silicic anhydride and 0.2 to 5% by weight magnesium stearate, and the density of the tablet is 1.12 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.9 mm, tablet thickness 4.7 to 5.1 mm, tablet volume 325 to 360 mm ³ , preferably total weight per tablet 385-425 mg tablets, 185-215 mg irbesartan, 0.75-9 wt% croscarmellose sodium, 25-60 wt% lactose and ligation Containing crystalline cellulose, 0.75-5% by weight hypromellose, 0.3-4.5% by weight light silicic anhydride and 0.3-4.5% by weight magnesium stearate, with a tablet density of 1 .13 to 1.23 mg / mm ³ , tablet band thickness 2.5 to 2.85 mm, tablet thickness 4.7 to 5.05 mm, tablet volume 325 to 350 mm ³ , more preferably per tablet 1.9-210 mg of irbesartan, 1-8% by weight of croscarmellose sodium, 30-50% by weight of lactose and crystalline cellulose, 1-4% by weight of hypromellose, 0. 5 to 4 containing by weight% of light anhydrous silicic acid and 0.5 to 4% by weight of magnesium stearate, the density of the tablet 1.15~1.23mg / mm ^3, the tablets Command thickness 2.5～2.8Mm, the thickness of the tablet 4.7～5.0Mm, a 325～345Mm ³ the volume of the tablet.

  The present preparation may contain a coating agent and may be any coating agent that can be used for pharmaceutical purposes. Specifically, hypromellose, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate Copolymer, Opadry, Carnauba wax, Carboxyvinyl polymer, Dry methacrylic acid copolymer, Dimethylaminoethyl methacrylate / methyl methacrylate copolymer, Stearyl alcohol, Shellac, Cetanol, Hydroxypropyl methylcellulose acetate succinate, Hydroxypropyl methylcellulose phthalate, Fumaric acid / stearic acid Polyvinyl acetal diethylamino acetate hydroxypropylmethylcellulose mixture, polyvinylacetal diethylamino acetate, polyvinyl alcohol, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, and the like.

  The content of the coating agent in this preparation is 0.05 to 10% by weight, preferably 0.075 to 5% by weight, more preferably 0.1 to 2.5% by weight, based on the total amount of the preparation.

  When the tablet is coated with the above coating agent, the preparation may contain a colorant and a plasticizer together with the coating agent. Any colorant or plasticizer may be used as long as it is pharmaceutically acceptable.

  Colorants include titanium oxide, yellow ferric oxide, ferric oxide, edible red No. 3, edible yellow No. 5, edible blue No. 1, etc., edible pigments, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, Riboflavin, powdered green tea powder, etc. are mentioned.

  Examples of the plasticizer include triethyl citrate and polyethylene glycol.

  Premix products that can be prepared by combining various additives such as coating agents, colorants and plasticizers can be used.

  This preparation can be produced by a conventional tablet production method. That is, this preparation is a method in which irbesartan and the above-mentioned additives are mixed with an appropriate mixer such as a V-type mixer to produce a mixed powder for tablets, and then the mixed powder is 1) directly compressed and compressed. Or 2) Granules, which can be produced by a method of compressing and compressing the granules.

  The granule used in the method of compressing and compressing the granule may be produced by an extrusion granulation method, a stirring granulation method, a fluidized bed granulation method, a dry granulation method or the like, but the stirring granulation method is preferred.

  A single tableting machine, a rotary tableting machine, or the like can be used as a machine for compressing and compressing mixed powder for tablets or granules of the mixed powder.

  The dosage form of this preparation should just be the tablet normally prescribed | regulated to the formulation rule of the Japanese Pharmacopoeia. In addition, the tablet can be provided with a score line and a mark for improving discrimination. Furthermore, the tablet of this preparation may be a round tablet or an atypical tablet.

  When this preparation is an atypical tablet, it may be defined by a short diameter, a long diameter, etc. In the present specification (see FIG. 1), “minor axis” refers to the diameter in the minor axis direction. The “major axis” is the diameter in the major axis direction. “Short diameter R1” is a part of the radius of curvature of the rounded portion arranged on the short diameter side, and is a portion rising from the side surface of the tablet. The “minor axis R2” is a part of the radius of curvature of the rounded portion arranged on the minor axis side, and is a part connecting the minor axes R1 on both sides. The “major axis R1” is a part of the radius of curvature of the rounded portion arranged on the major axis side, and is a part that rises from the side surface of the tablet. The “major axis R2” is a part of the radius of curvature of the rounded portion arranged on the major axis side, and is a part connecting the minor axes R1 on both sides. “Cup depth” represents the height of only the round part of the tablet, and is the distance from the top or bottom of the flat part on the side of the tablet to the top of the tablet.

  When this formulation is an atypical tablet, the minor axis is 2.5 to 10 mm, preferably 3.75 to 10 mm, more preferably 5 to 10 mm. The major axis is 5 to 20 mm, preferably 7.5 to 20 mm, more preferably 10 to 20 mm. The minor axis R1 is 0.5 to 5 mm, preferably 0.75 to 5 mm, more preferably 1 to 5 mm. The minor axis R2 is 0.25 to 10 mm, preferably 0.5 to 10 mm, more preferably 1 to 10 mm. The major axis R1 is 0.25 to 5 mm, preferably 0.5 to 5 mm, more preferably 1 to 5 mm. The major axis R2 is 10 to 40 mm, preferably 20 to 40 mm, more preferably 30 to 40 mm. Cup depth is 0.25 to 2 mm, preferably 0.5 to 2 mm, more preferably 1 to 2 mm.

  By changing the major axis, minor axis, R of the tablet, or cup depth, the density of the tablet can be adjusted, and thus the disintegration time can be adjusted.

  The disintegration time of the tablet of this preparation may be within the range where the absorbability of the drug is lowered and the dispersion of absorption is not large, but it is 7 minutes or less, preferably 6 minutes or less, more preferably 5 minutes or less. is there. If it is longer than this disintegration time, the absorbability of the drug is lowered, and the dispersion in absorption may be increased.

  The dissolution of the tablet of this preparation may be within the range where the drug absorption does not decrease, but in the first solution of the Japanese Pharmacopoeia dissolution test, the dissolution rate of irbesartan after 30 minutes from the start of the dissolution test is 85% or more. . On the other hand, in the second solution of the Japanese Pharmacopoeia dissolution test, the dissolution rate of irbesartan 30 minutes after the start of the dissolution test is 70% or more. Preferably, in the first solution of the Japanese Pharmacopoeia dissolution test, the dissolution rate of irbesartan 30 minutes after the start of the dissolution test is 85% or more, and in the second solution of the Japanese Pharmacopoeia dissolution test, the irbesartan 30 minutes after the start of the dissolution test. The elution rate of is 70% or more. If the dissolution rate is lower than this, the drug absorbability may be lowered.

  The hardness of the tablet of the present preparation is usually about 10 to 400N, preferably 50 to 300N, more preferably about 100 to 200N when measured with a hardness meter. If the hardness is lower than this, the tablet may be damaged during storage or when the tablet is taken out from the PTP package, and if it is higher, the disintegration time of the tablet may be extended.

（４）結果
錠剤密度を変更した錠剤のバンド厚み、体積、表面積、崩壊時間および錠剤硬度を表２に、錠剤密度と崩壊時間の関係を図２に示す。その結果、錠剤密度が大きくなれば、崩壊時間が速くなるが、錠剤密度が１．２０ｍｇ／ｍｍ^３よりも大きくなれば、崩壊時間が遅くなり、錠剤密度が１．２３ｍｇ／ｍｍ^３の場合、崩壊時間が３００秒以上となった。従って、崩壊時間を３００秒以内に調整する場合、錠剤密度は、１．１２〜１．２３ｍｇ／ｍｍ^３が最適であった。また、実施例３と比較例１の溶出挙動を比較すると、崩壊時間が速い実施例３で溶出率が速くなった。上記実施例２の錠剤を下記の表４の処方でコーティングすることができる。

EXAMPLES Hereinafter, although an Example, a comparative example, and a reference example are given and this invention is demonstrated in detail, this invention is not restrict | limited by these. The tablets produced were measured for the disintegration time, hardness and dissolution rate of the tablets by the following test methods.
(1) Tablet production method Table 1 shows the tablet formulation. Tablets were produced so that the amount of irbesartan per tablet was 200 mg and the total tablet weight was 400 mg. That is, irbesartan, lactose, crystalline cellulose, croscarmellose sodium and hypromellose were added and granulated using a high-speed agitation granulator (Fukae Pautech Earth Technic Co., Ltd.). The obtained granulated material was put into a fluidized bed granulator / dryer (manufactured by POWREC), dried at an air supply temperature of 85 ° C., and then sized using a power mill (manufactured by Showa Chemical Machinery Co., Ltd.). To the granulated granules, croscarmellose sodium, light anhydrous silicic acid and magnesium stearate were added and mixed, and the resulting tablet granule was used as a tableting tablet (major axis x minor axis, 14 x 7.3 mm). The tablet was obtained by static compression using a single tableting machine (manufactured by JT Toshi) at a tableting pressure of 4 to 16 kN. By adjusting the tableting pressure, the tablet band thickness was changed and the tablet density was adjusted.
(2) Disintegration test method The fifteenth revised Japanese Pharmacopoeia disintegration test method was applied mutatis mutandis, and the disintegration time without an auxiliary panel was measured using purified water specified by the Japanese Pharmacopoeia. The test is performed with 3 tablets, and the average value is shown. The disintegration time was set to 300 seconds (5 minutes) or less in consideration of the absorbability of irbesartan.
(3) Hardness test method The hardness of the tablet was measured using a tablet hardness tester (manufactured by ERWEKA International AG). The test is performed with 6 to 10 tablets, and the average value is shown.
(4) Dissolution test method This test method measures the dissolution rate of irbesartan in tablets. Using a dissolution test apparatus, using 900 mL of the Japanese Pharmacopoeia Second Solution (pH 6.8) as the test solution, conducted at 50 rpm per minute according to the 16th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) It was.
The eluate 10 minutes, 20 minutes, 30 minutes and 40 minutes after the start of the dissolution test was filtered through a filter having a pore diameter of 0.45 μm, and the absorbance was measured at an absorption wavelength of 244 nm using an ultraviolet absorptiometer.
Separately, about 44 mg of irbesartan standard substance was accurately weighed and 20 mL of methanol was added. Furthermore, the second solution of JP dissolution test was added to make exactly 200 mL to obtain a standard solution.
(5) Measurement of tablet density, volume, surface area, band thickness and thickness Tablet density, volume and surface area were measured by tablet volume / surface area simulation software (Tablet CAD). The tablet band thickness was measured with calipers, and the tablet thickness was measured with a thickness gauge.

(4) Results Table 2 shows the band thickness, volume, surface area, disintegration time, and tablet hardness of the tablet with the changed tablet density, and FIG. 2 shows the relationship between the tablet density and the disintegration time. As a result, if the tablet density is increased, the disintegration time is faster, but if the tablet density is greater than 1.20 mg / mm ³ , the disintegration time is delayed, and if the tablet density is 1.23 mg / mm ³ , The decay time was over 300 seconds. Therefore, when adjusting the disintegration time within 300 seconds, the tablet density was optimally 1.12 to 1.23 mg / mm ³ . Moreover, when the elution behaviors of Example 3 and Comparative Example 1 were compared, the elution rate was faster in Example 3 where the disintegration time was faster. The tablet of Example 2 above can be coated with the formulation in Table 4 below.

  According to the present invention, by controlling the density of the irbesartan-containing tablet, it is possible to provide a tablet that rapidly disintegrates. Moreover, it becomes possible to provide a practical formulation about the hardness and dissolution property of a tablet.

Claims (12)

Tablets containing irbesartan and croscarmellose sodium as a disintegrant, tablet density of 1.12 to 1.23 mg / mm ³ , irbesartan content of 180 to 220 mg, and total tablet weight of 380 to 430 mg. The tablet according to claim 1, wherein the tablet volume is 320 to 360 mm ³ . The tablet according to claim 1, wherein the tablet has a band thickness of 2.5 to 2.9 mm. The tablet according to claim 1, wherein the tablet has a thickness of 4.7 to 5.1 mm. The tablet according to claim 1, wherein the tablet volume is 320 to 360 mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness is 4.7 to 5.1 mm. Furthermore, the tablet in any one of Claims 1-5 containing lactose, crystalline cellulose, hypromellose, light silicic acid anhydride, and a magnesium stearate. Further, it contains lactose, crystalline cellulose, hypromellose, light anhydrous silicic acid and magnesium stearate, the tablet volume is 320 to 360 mm ³ , the tablet band thickness is 2.5 to 2.9 mm, and the tablet thickness is 4.7. It is-5.1 mm, The tablet in any one of Claims 1-5. The tablet according to any one of claims 1 to 7, wherein the disintegration time of the tablet is within 7 minutes. The tablet according to any one of claims 1 to 8, wherein in the first solution of the Japanese Pharmacopoeia dissolution test, the dissolution rate of irbesartan 30 minutes after the start of the dissolution test is 85% or more. The tablet according to any one of claims 1 to 8, wherein in the second solution of the Japanese Pharmacopoeia dissolution test, the dissolution rate of irbesartan 30 minutes after the start of the dissolution test is 70% or more. The dissolution rate of irbesartan 30 minutes after the start of the dissolution test in the first solution of the Japanese Pharmacopoeia is 85% or more, and the dissolution rate of irbesartan 30 minutes after the start of the dissolution test in the second solution of the Japanese Pharmacopoeia Is 70% or more, The tablet according to any one of claims 1 to 8. The film coating tablet which coat | covered the tablet in any one of Claims 1-11 with the hypromellose.

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